The IL-6 family of cytokines, which includes OSM (oncostatin M) and LIF (leukaemia inhibitory factor), signals through the common gp130 (glycoprotein 130) receptor chain to activate STAT3.
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STAT3 (signal transducer and activator of transcription 3), initially identified as an acute-phase response factor binding to the acute-phase response element in IL (interleukin)-6-stimulated hepatocytes, is a pleiotropic transcription factor capable of mediating rapid changes in gene expression following cytokine, hormone or growth factor stimulation. These results highlight STAT3β as a significant transcriptional regulator in its own right, with additional actions to cross-regulate STAT3α phosphorylation and nuclear retention after cytokine stimulation. The physiological importance of prolonged phosphorylation and nuclear retention was indicated by transcriptome profiling of STAT3 −/− cells expressing either STAT3α or STAT3β, revealing the complexity of genes that are up- and down-regulated by the STAT3 spliceforms, including a distinct set of STAT3β-specific genes regulated under basal conditions and after cytokine stimulation. Importantly, co-expression of the spliceforms revealed that STAT3β enhanced and prolonged the phosphorylation and nuclear retention of STAT3α, but a STAT3β R609L mutant, with a disrupted SH2 (Src homology 2) domain, was not tyrosine phosphorylated following cytokine stimulation and could not cross-regulate STAT3α. Notably, the sustained nuclear translocation and phosphorylation of STAT3β following cytokine exposure contrasted with a transient nuclear translocation and phosphorylation of STAT3α. We have expressed STAT3α and STAT3β at comparable levels to facilitate a direct comparison of their functional effects, and have shown their different cytokine-stimulated kinetics of phosphorylation and nuclear translocation. Although a shorter STAT3β spliceform was initially described as a negative regulator of STAT3α, gene knockout studies have revealed that both forms play critical roles. Phosphorylation of STAT3 (signal transducer and activator of transcription 3) is critical for its nuclear import and transcriptional activity.
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